The objectives of this research proposal are as follows: 1. To define and characterize the alteration in hepatic drug elimination caused by cimetidine. We will determine the relationship to dose of cimetidine, time course of onset and recovery, as well as which pathway of elimination is most affected. These aspects will be studied in vivo in human volunteers and in the rat. In vitro experiments will be carried out using microsomes and liver perfusion to define the mechanism of the inhibition. 2. To define and characterize the interaction of cimetidine and other antihistamines with CNS receptors; if an interaction (for instance competitive inhibition) can be defined, we wish to determine whether the interaction is the cause of the depression of mental state observed clinically with cimetidine and other antihistamines. 3. To define and characterize the inhibition of tubular secretion found with cimetidine.